The flight response impairs cytoprotective mechanisms by activating the insulin pathway.

An animal's stress response requires different adaptive strategies depending on the nature and duration of the stressor. Whereas acute stressors, such as predation, induce a rapid and energy-demanding fight-or-flight response, long-term environmental stressors induce the gradual and long-lasting activation of highly conserved cytoprotective processes1-3. In animals across the evolutionary spectrum, continued activation of the fight-or-flight response weakens the animal's resistance to environmental challenges4,5. However, the molecular and cellular mechanisms that regulate the trade-off between the flight response and long-term stressors are poorly understood. Here we show that repeated induction of the flight response in Caenorhabditis elegans shortens lifespan and inhibits conserved cytoprotective mechanisms. The flight response activates neurons that release tyramine, an invertebrate analogue of adrenaline and noradrenaline. Tyramine stimulates the insulin-IGF-1 signalling (IIS) pathway and precludes the induction of stress response genes by activating an adrenergic-like receptor in the intestine. By contrast, long-term environmental stressors, such as heat or oxidative stress, reduce tyramine release and thereby allow the induction of cytoprotective genes. These findings demonstrate that a neural stress hormone supplies a state-dependent neural switch between acute flight and long-term environmental stress responses and provides mechanistic insights into how the flight response impairs cellular defence systems and accelerates ageing.

Integrating Data Across Multiple Sites in the Northeastern United States to Examine Associations Between a Prenatal Metal Mixture and Child Cognition.

We applied a novel hierarchical Bayesian weighted quantile sum (HBWQS) regression to combine data across 3 study sites to examine associations between prenatal exposure to metals and cognitive functioning in childhood. Data from 326 mother-child dyads enrolled in an ongoing cohort study, the Programming of Intergenerational Stress Mechanisms (PRISM) Study, based in New York, New York (recruitment in 2013-2020) and Boston, Massachusetts (recruitment 2011-2013), and the First Thousand Days of Life (FTDL) cohort study (recruitment 2012-2019), based in northern Virginia, were used. Arsenic, cadmium, manganese, lead, and antimony were measured in urine collected during pregnancy. Cognitive functioning was assessed in children aged 3-11 years using the National Institutes of Health Toolbox Cognition Battery. The HBWQS regression showed a negative association between the urinary metal mixture and the Cognition Early Childhood Composite Score in the PRISM New York City (ß = -3.67, 95% credible interval (CrI): -7.61, -0.01) and FTDL (ß = -3.76, 95% CrI: -7.66, -0.24) samples, with a similar trend in the PRISM Boston sample (ß = -3.24, 95% CrI: -6.77, 0.144). We did not detect these associations in traditionally pooled models. HBWQS regression allowed us to account for site heterogeneity and detect associations between prenatal metal-mixture exposure and cognitive outcomes in childhood. Given the ubiquity of metals exposure, interventions aimed at reducing prenatal exposure may improve cognitive outcomes in children. This article is part of a Special Collection on Environmental Epidemiology.

Changes in depressive and anxiety symptoms during COVID-19 in children from the PROGRESS cohort.

BACKGROUND: We assessed associations between maternal stress, social support, and child resiliency during the COVID-19 pandemic in relation to changes in anxiety and depression symptoms in children in Mexico City. METHODS: Participants included 464 mother-child pairs from a longitudinal birth cohort in Mexico City. At ages 8-11 (pre-COVID, 2018-2019) and 9-12 (during COVID, May-Nov 2020) years, depressive symptoms were assessed using the child and parent-reported Children's Depressive Inventory. Anxiety symptoms were assessed using the child-reported Revised Manifest Anxiety Scale. Linear regression models were used to estimate associations between maternal stress, social support, and resiliency in relation to changes in depressive and anxiety symptoms. We additionally assessed outcomes using clinically relevant cut-points. Models were adjusted for child age and sex and maternal socioeconomic status and age. RESULTS: Higher continuous maternal stress levels during the COVID-19 pandemic were associated with increases in depressive symptoms (ß: 0.72; 95% CI: 0.12, 1.31), and higher odds of clinically relevant depressive and anxiety symptoms in the children. CONCLUSIONS: Maternal stress during the pandemic may increase mental health symptoms in pre-adolescent children. Additional studies are needed that examine the long-term pandemic-related impacts on mental health throughout the adolescent years. IMPACT: In this longitudinal cohort study of children in Mexico City, we observed that depressive symptoms were higher from before to during the pandemic. Maternal stress surrounding the pandemic may increase mental health symptoms in pre-adolescent children. Child resiliency may help to protect against pandemic-related stressors.

Association between prenatal metal exposure and adverse respiratory symptoms in childhood.

INTRODUCTION: Manganese and lead have been cross-sectionally associated with adverse respiratory outcomes in childhood but there is limited data on their combined effects starting in utero. We examined associations between in utero exposure to metals and childhood respiratory symptoms. METHODS: We assessed 633 mother-child dyads enrolled in the Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) birth cohort in Mexico City. Blood manganese (BMn) and lead (BPb) were measured in mothers at 2nd and 3rd trimester. Ever wheeze, current wheeze and asthma diagnosis were ascertained at 4-5 and 6-7 year visits through the International Study of Asthma and Allergies in Childhood survey. Logistic mixed model regression was used to assess the association between prenatal metals and respiratory outcomes in children across the 4-5 and 6-7 year visits. Covariates included mother's age, education and asthma, environmental tobacco smoke, child's sex and assessment time. RESULTS: In adjusted models, higher 2nd trimester BPb had a significant association with elevated odds of ever wheeze (Odds Ratio (OR): 1.97, 95% CI: 1.05, 3.67). BMn at 2nd trimester was associated with decreased (OR: 0.06, 95% CI: 0.01, 0.35) odds of current wheeze. We did not find any statistically significant associations with 3rd trimester blood metals. CONCLUSION: Prenatal exposure to Pb was associated with higher odds of ever wheeze while Mn was negatively associated with odds of current wheeze. These findings underscore the need to consider prenatal metal exposure, including low exposure levels, in the study of adverse respiratory outcomes.

Prenatal lead exposure and childhood lung function: Influence of maternal cortisol and child sex.

INTRODUCTION: Maternal hypothalamic-pituitary-adrenal (HPA) axis disruption in pregnancy may contribute to the programming of childhood respiratory disease and may modify the effect of chemical toxins, like lead (Pb), on lung development. Child sex may further modify these effects. We sought to prospectively examine associations between maternal HPA axis disruption, prenatal Pb and childhood lung function and explore potential effect modification by maternal cortisol and child sex on the association between prenatal Pb and lung function outcomes. MATERIALS AND METHODS: Analyses included 222 mothers and children enrolled in a longitudinal birth cohort study in Mexico City. Maternal diurnal salivary cortisol was assessed in pregnancy; cortisol awakening response (CAR) and diurnal slope were calculated. Blood Pb was measured during the second trimester of pregnancy. Post-bronchodilator lung function was tested at ages 8-11 years. Associations were modeled using generalized linear models with interaction terms, adjusting for covariates. RESULTS: A higher (flatter) diurnal slope was associated with lower FEV1/FVC ratio (ß: 0.433, 95%CI [-0.766, -0.101]). We did not find any main effect associations between prenatal Pb and lung function outcomes. We report an interaction between Pb and cortisol in relation to FEV1/FVC and FEF25-75% (pinteraction<0.05 for all). Higher prenatal Pb was associated with reduced FEV1/FVC only in children whose mothers had a high CAR. Higher prenatal Pb was also associated with reduced FEV1/FVC and FEF25-75% in mothers with a flatter diurnal slope. A 3-way interaction between prenatal Pb, CAR and sex on FEV1/FVC, indicated that boys born to women with high CAR and higher prenatal Pb levels had lower FEV1/FVC ratios (pinteraction = 0.067). CONCLUSIONS: Associations between prenatal Pb and childhood lung function were modified by disrupted maternal cortisol in pregnancy and child sex. These findings underscore the need to consider complex interactions to fully elucidate effects of prenatal Pb exposure on childhood lung function.

Prenatal lead exposure, telomere length in cord blood, and DNA methylation age in the PROGRESS prenatal cohort.

BACKGROUND: Lead is a ubiquitous pollutant with deleterious effects on human health and remains a major current public health concern in developing countries. This heavy metal may interfere with nucleic acids via oxidative stress or epigenetic changes that affect biological markers of aging, e.g., telomere length and DNA methylation (DNAm). Telomere shortening associates with biological age in newborns, and DNA methylation at specific CpG sites can be used to calculate "epigenetic clocks". OBJECTIVE: The aim of this study was to examine the associations of prenatal lead exposures with telomere length and DNA-methylation-based predictors of age in cord blood. DESIGN: The study included 507 mother-child pairs from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a birth cohort in Mexico City. Maternal blood (second trimester, third trimester and at delivery) and bone lead levels (one month postpartum) were measured using inductively coupled plasma-mass spectrometry and X-ray fluorescence, respectively. Cord blood leukocyte telomere length was measured using quantitative PCR and apparent age by DNA methylation biomarkers, i.e., Horvath's DNA methylation age and the Knight's predictor of gestational age. RESULTS: Average maternal age was 28.5 ± 5.5 years, and 51.5% reported low socioeconomic status. Children's mean telomere length was 1.2 ± 1.3 relative units, and mean DNA methylation ages using the Horvath's and Knight's clocks were -2.6 ± 0.1 years and 37.9 ± 1.4 weeks (mean ± SD), respectively. No significant associations were found between maternal blood and bone lead concentrations with telomere length and DNAm age in newborns. CONCLUSION: We found no associations of prenatal lead exposure with telomere length and DNA methylation age biomarkers.

Critical windows of perinatal particulate matter (PM2.5) exposure and preadolescent kidney function.

Air pollution exposure, especially particulate matter ≤2.5 µm in diameter (PM2.5), is associated with poorer kidney function in adults and children. Perinatal exposure may occur during susceptible periods of nephron development. We used distributed lag nonlinear models (DLNMs) to examine time-varying associations between early life daily PM2.5 exposure (periconceptional through age 8 years) and kidney parameters in preadolescent children aged 8-10 years. Participants included 427 mother-child dyads enrolled in the PROGRESS birth cohort study based in Mexico City. Daily PM2.5 exposure was estimated at each participant's residence using a validated satellite-based spatio-temporal model. Kidney function parameters included estimated glomerular filtration rate (eGFR), serum cystatin C, and blood urea nitrogen (BUN). Models were adjusted for child's age, sex and body mass index (BMI) z-score, as well as maternal education, indoor smoking report and seasonality (prenatal models were additionally adjusted for average first year of life PM2.5 exposure). We also tested for sex-specific effects. Average perinatal PM2.5 was 22.7 µg/m3 and ranged 16.4-29.3 µg/m3. Early pregnancy PM2.5 exposures were associated with higher eGFR in preadolescence. Specifically, we found that PM2.5 exposure between weeks 1-18 of gestation was associated with increased preadolescent eGFR, whereas exposure in the first 14 months of life after birth were associated with decreased eGFR. Specifically, a 5 µg/m3 increase in PM2.5 during the detected prenatal window was associated with a cumulative increase in eGFR of 4.44 mL/min/1.732 (95%CI: 1.37, 7.52), and during the postnatal window we report a cumulative eGFR decrease of -10.36 mL/min/1.732 (95%CI: -17.68, -3.04). We identified perinatal windows of susceptibility to PM2.5 exposure with preadolescent kidney function parameters. Follow-up investigating PM2.5 exposure with peripubertal kidney function trajectories and risk of kidney disease in adulthood will be critical.

Prenatal and early life exposure to particulate matter, environmental tobacco smoke and respiratory symptoms in Mexican children.

BACKGROUND: Exposure to particulate matter <2.5 µm in diameter (PM2.5) and environmental tobacco smoke (ETS) are associated with respiratory morbidity starting in utero. However, their potential synergistic effects have not been completely elucidated. Here, we examined the joint effects of prenatal and early life PM2.5 and prenatal ETS exposure on respiratory outcomes in children. MATERIAL AND METHODS: We studied 536 mother-child dyads in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study in Mexico City. Exposure to PM2.5 was estimated using residence in pregnancy and child's first year of life with a satellite-based spatio-temporal model. ETS exposure was assessed by caregiver's report of any smoker in the household during the second or third trimester. Outcomes included report of ever wheeze and wheeze in the past 12 months (current wheeze) assessed when children were 6-8 years old considered in separate models. Associations were modeled using distributed lag models (DLM) with daily PM2.5 averages for pregnancy and the first year of life, adjusting for child's sex, birth weight z-score, mother's age and education at enrollment, maternal asthma, season of conception and stratified by prenatal ETS exposure (yes/no). RESULTS: We identified a sensitive window from gestational week 14 through postnatal week 18 during which PM2.5 was associated with higher risk of ever wheeze at age 6-8 years. We also observed a critical window of PM2.5 exposure between postnatal weeks 6-39 and higher risk of current wheeze. We found significant associations between higher prenatal and early life PM2.5 exposure and higher cumulative risk ratios of ever wheeze (RR:3.76, 95%CI [1.41, 10.0] per 5 µg/m3) and current wheeze in the past year (RR:7.91, 95%CI [1.5, 41.6] per 5 µg/m3) only among children born to mothers exposed to ETS in pregnancy when compared to mothers who were not exposed. CONCLUSIONS: Exposure to prenatal ETS modified the association between prenatal and early life PM2.5 exposure and respiratory outcomes at age 6-8 years. It is important to consider concurrent chemical exposures to more comprehensively characterize children's environmental risk. Interventions aimed at decreasing passive smoking might mitigate the effects of ambient air pollution.

Placental gene networks at the interface between maternal PM2.5 exposure early in gestation and reduced infant birthweight.

BACKGROUND: A growing body of evidence links maternal exposure to particulate matter <2.5 µM in diameter (PM2.5) and deviations in fetal growth. Several studies suggest that the placenta plays a critical role in conveying the effects of maternal PM2.5 exposure to the developing fetus. These include observed associations between air pollutants and candidate placental features, such as mitochondrial DNA content, DNA methylation and telomere length. However, gaps remain in delineating the pathways linking the placenta to air pollution-related health effects, including a comprehensive profiling of placental processes impacted by maternal PM2.5 exposure. In this study, we examined alterations in a placental transcriptome-wide network in relation to maternal PM2.5 exposure prior to and during pregnancy and infant birthweight. METHODS: We evaluated PM2.5 exposure and placental RNA-sequencing data among study participants enrolled in the Rhode Island Child Health Study (RICHS). Daily residential PM2.5 levels were estimated using a hybrid model incorporating land-use regression and satellite remote sensing data. Distributed lag models were implemented to assess the impact on infant birthweight due to PM2.5 weekly averages ranging from 12 weeks prior to gestation until birth. Correlations were assessed between PM2.5 levels averaged across the identified window of susceptibility and a placental transcriptome-wide gene coexpression network previously generated using the WGCNA R package. RESULTS: We identified a sensitive window spanning 12 weeks prior to and 13 weeks into gestation during which maternal PM2.5 exposure is significantly associated with reduced infant birthweight. Two placental coexpression modules enriched for genes involved in amino acid transport and cellular respiration were correlated with infant birthweight as well as maternal PM2.5 exposure levels averaged across the identified growth restriction window. CONCLUSION: Our findings suggest that maternal PM2.5 exposure may alter placental programming of fetal growth, with potential implications for downstream health effects, including susceptibility to cardiometabolic health outcomes and viral infections.

Prenatal polyunsaturated fatty acids and child asthma: Effect modification by maternal asthma and child sex.

BACKGROUND: Findings on prenatal polyunsaturated fatty acid (PUFA) intake and child wheeze and asthma have been inconsistent. OBJECTIVE: We sought to examine associations between prenatal PUFA status and child wheeze/asthma and modifying effects of maternal asthma/atopy, child sex, and maternal race. METHODS: Analyses included 1019 mother-child dyads with omega-3 (n-3) and omega-3 (n-6) PUFAs measured in second-trimester plasma; n-6/n-3 ratios were calculated. Child wheeze/asthma outcomes ascertained at age 4 to 6 years included ever physician-diagnosed asthma, current wheeze (symptoms past 12 months), current asthma (diagnosis and medication and/or symptoms past 12 months), and current diagnosed asthma. Each PUFA indicator and outcome was analyzed in separate models using modified Poisson regression with interaction terms. RESULTS: In quartile (Q) analyses, higher n-6 PUFAs were associated with increased risk of ever (risk ratio [RR] high vs low [RR Q4 vs Q1], 1.70; 95% CI, 1.07-2.71) and current (RR Q4 vs Q1, 1.70; 95% CI, 1.07-2.71) diagnosed asthma, whereas n-3 PUFAs were associated with lower risk (RR Q4 vs Q1, 0.59; 95% CI, 0.33-1.03) of current diagnosed asthma (Ptrend < .05 for all). Higher n-6 PUFAs were associated with a higher risk of all respiratory outcomes among children born to women with asthma (Pinteraction < .05 for all outcomes). A significant 3-way interaction between child sex, maternal asthma, and n-6/n-3 PUFA indicated that male children born to women with asthma and a higher ratio had the highest risk across wheeze/asthma outcomes (Pinteraction < .05). CONCLUSIONS: Associations between prenatal PUFA status and childhood wheeze/asthma were modified by maternal history of asthma and child sex.

Identifying critical windows of prenatal particulate matter (PM2.5) exposure and early childhood blood pressure.

BACKGROUND: Exposure to air pollution is associated with increased blood pressure (BP) in adults and children. Some evidence suggests that air pollution exposure during the prenatal period may contribute to adverse cardiorenal health later in life. Here we apply a distributed lag model (DLM) approach to identify critical windows that may underlie the association between prenatal particulate matter ≤ 2.5 µm in diameter (PM2.5) exposure and children's BP at ages 4-6 years. METHODS: Participants included 537 mother-child dyads enrolled in the Programming Research in Obesity, GRowth Environment, and Social Stress (PROGRESS) longitudinal birth cohort study based in Mexico City. Prenatal daily PM2.5 exposure was estimated using a validated satellite-based spatio-temporal model and BP was measured using the automated Spacelabs system with a sized cuff. We used distributed lag models (DLMs) to examine associations between daily PM2.5 exposure and systolic and diastolic BP (SBP and DBP), adjusting for child's age, sex and BMI, as well as maternal education, preeclampsia and indoor smoking report during the second and third trimester, seasonality and average postnatal year 1 PM2.5 exposure. RESULTS: We found that PM2.5 exposure between weeks 11-32 of gestation (days 80-226) was significantly associated with children's increased SBP. Similarly, PM2.5 exposure between weeks 9-25 of gestation (days 63-176) was significantly associated with increased DBP. To place this into context, a constant 10 µg/m3 increase in PM2.5 sustained throughout this critical window would predict a cumulative increase of 2.6 mmHg (CI: 0.5, 4.6) in SBP and 0.88 mmHg (CI: 0.1, 1.6) in DBP at ages 4-6 years. In a stratified analysis by sex, this association persisted in boys but not in girls. CONCLUSIONS: Second and third trimester PM2.5 exposure may increase children's BP in early life. Further work investigating PM2.5 exposure with BP trajectories later in childhood will be important to understanding cardiorenal trajectories that may predict adult disease. Our results underscore the importance of reducing air pollution exposure among susceptible populations, including pregnant women.

ß-cyclodextrin coating: improving biocompatibility of magnetic nanocomposites for biomedical applications.

The role Beta-cyclodextrin (ßCD) on improving biocompatibility on healthy cellular and animal models was studied upon a formulation obtained from the development of a simple coating procedure. The obtained nanosystems were thoroughly characterized by FTIR, TGA, atomic absorption spectroscopy, dynamic light scattering and zeta potential, TEM/HR-TEM and magnetic properties. ßCD might interact with the magnetic core through hosting OA. It is feasible that the nanocomposite is formed by nanoparticles of MG@OA dispersed in a ßCD matrix. The evaluation of ßCD role on biocompatibility was performed on two healthy models. To this end, in vivo studies were carried out on Caenorhabditis elegans. Locomotion and progeny were evaluated after exposure animals to MG, MG@OA, and MG@OA-ßCD (10 to 500 µg/mL). The influence of ßCD on cytotoxicity was explored in vitro on healthy rat aortic endothelial cells, avoiding alteration in the results derived from the use of transformed cell lines. Biological studies demonstrated that ßCD attaching improves MG biocompatibility.

Sex-specific associations between prenatal negative life events and birth outcomes.

Maternal psychosocial stress can negatively impact gestational length and development of the fetus. These effects may be sex-specific but have not been extensively studied. The objective of this study was to examine the associations between prenatal maternal stress and birth outcomes and whether effects are modified by sex. Prenatal maternal stress was indexed by a maternal negative life events (NLEs) score ascertained in 527 urban mothers; a higher NLE score indicates greater stress. Birth outcomes included gestational age, preterm birth (PTB) (<37 weeks), and birthweight for gestational age z-scores. Modified Poisson regression and linear models were used to evaluate associations of prenatal NLE scores with birth outcomes. Sex differences were assessed by inclusion of an interaction term for sex by NLE score and in sex-stratified analyses. In analyses adjusted for maternal age, education, race/ethnicity, and pre-pregnancy body mass index (BMI), increasing prenatal stress was associated with shortened gestational age (days) (ß = -0.63, [95% CI -1.20, -0.06]). This effect was sex specific, with increasing prenatal stress associated with shortened gestational age, as well as increased risk of PTB, in male infants (ß = -1.35 [95% CI -2.17, -0.54] and RR = 1.18 [95% CI 0.99, 1.42], respectively) but not female infants (ß = 0.15 [95%CI -0.63, 0.94] and RR = 0.85, [95%CI 0.65, 1.11], respectively). Prenatal stress was not associated with birthweight z-scores. Our results support the importance of psychosocial stress as a programming factor that may have sex-specific effects for adverse fetal outcomes. Understanding sex-specific effects of prenatal stress on birth outcomes may inform prevention strategies. LAY SUMMARY Higher stress experienced by mothers in pregnancy was associated with shorter length of pregnancy and the effect was stronger in male infants when compared to female infants.

Association between prenatal particulate air pollution exposure and telomere length in cord blood: Effect modification by fetal sex.

INTRODUCTION: In utero particulate matter exposure produces oxidative stress that impacts cellular processes that include telomere biology. Newborn telomere length is likely critical to an individual's telomere biology; reduction in this initial telomere setting may signal increased susceptibility to adverse outcomes later in life. We examined associations between prenatal particulate matter with diameter ≤2.5 µm (PM2.5) and relative leukocyte telomere length (LTL) measured in cord blood using a data-driven approach to characterize sensitive windows of prenatal PM2.5 effects and explore sex differences. METHODS: Women who were residents of Mexico City and affiliated with the Mexican Social Security System were recruited during pregnancy (n = 423 for analyses). Mothers' prenatal exposure to PM2.5 was estimated based on residence during pregnancy using a validated satellite-based spatio-temporally resolved prediction model. Leukocyte DNA was extracted from cord blood obtained at delivery. Duplex quantitative polymerase chain reaction was used to compare the relative amplification of the telomere repeat copy number to single gene (albumin) copy number. A distributed lag model incorporating weekly averages for PM2.5 over gestation was used in order to explore sensitive windows. Sex-specific associations were examined using Bayesian distributed lag interaction models. RESULTS: In models that included child's sex, mother's age at delivery, prenatal environmental tobacco smoke exposure, pre-pregnancy BMI, gestational age, birth season and assay batch, we found significant associations between higher PM2.5 exposure during early pregnancy (4-9 weeks) and shorter LTL in cord blood. We also identified two more windows at 14-19 and 34-36 weeks in which increased PM2.5 exposure was associated with longer LTL. In stratified analyses, the mean and cumulative associations between PM2.5 and shortened LTL were stronger in girls when compared to boys. CONCLUSIONS: Increased PM2.5 during specific prenatal windows was associated with shorter LTL and longer LTL. PM2.5 was more strongly associated with shortened LTL in girls when compared to boys. Understanding sex and temporal differences in response to air pollution may provide unique insight into mechanisms.

Prenatal fine particulate exposure and early childhood asthma: Effect of maternal stress and fetal sex.

BACKGROUND: The impact of prenatal ambient air pollution on child asthma may be modified by maternal stress, child sex, and exposure dose and timing. OBJECTIVE: We prospectively examined associations between coexposure to prenatal particulate matter with an aerodynamic diameter of less than 2.5 microns (PM2.5) and maternal stress and childhood asthma (n = 736). METHODS: Daily PM2.5 exposure during pregnancy was estimated using a validated satellite-based spatiotemporally resolved prediction model. Prenatal maternal negative life events (NLEs) were dichotomized around the median (high: NLE ≥ 3; low: NLE < 3). We used Bayesian distributed lag interaction models to identify sensitive windows for prenatal PM2.5 exposure on children's asthma by age 6 years, and determine effect modification by maternal stress and child sex. RESULTS: Bayesian distributed lag interaction models identified a critical window of exposure (19-23 weeks' gestation, cumulative odds ratio, 1.15; 95% CI, 1.03-1.26; per interquartile range [1.7 µg/m3] increase in prenatal PM2.5 level) during which children concomitantly exposed to prenatal PM2.5 and maternal stress had increased risk of asthma. No significant association was seen in children born to women reporting low prenatal stress. When examining modifying effects of prenatal stress and fetal sex, we found that boys born to mothers with higher prenatal stress were most vulnerable (19-21 weeks' gestation; cumulative odds ratio, 1.28; 95% CI, 1.15-1.41; per interquartile range increase in PM2.5). CONCLUSIONS: Prenatal PM2.5 exposure during sensitive windows is associated with increased risk of child asthma, especially in boys concurrently exposed to elevated maternal stress.

Prenatal fine particulate exposure associated with reduced childhood lung function and nasal epithelia GSTP1 hypermethylation: Sex-specific effects.

BACKGROUND: In utero exposure to particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) has been linked to child lung function. Overlapping evidence suggests that child sex and exposure timing may modify effects and associations may be mediated through glutathione S-transferase P1 (GSTP1) methylation. METHODS: We prospectively examined associations among prenatal PM2.5 exposure and child lung function and GSTP1 methylation in an urban pregnancy cohort study. We employed a validated satellite-based spatiotemporally resolved prediction model to estimate daily prenatal PM2.5 exposure over gestation. We used Baysian distributed lag interaction models (BDLIMs) to identify sensitive windows for prenatal PM2.5 exposure on child lung function and nasal epithelia GSTP1 methylation at age 7 years, and to examine effect modification by child sex. RESULTS: BDLIMs identified a sensitive window for prenatal PM2.5 exposure at 35-40 weeks gestation [cumulative effect estimate (CEE) = - 0.10, 95%CI = - 0.19 to - 0.01, per µg/m3 increase in PM2.5] and at 36-40 weeks (CEE = - 0.12, 95%CI = - 0.20 to - 0.01) on FEV1 and FVC, respectively, in boys. BDLIMs also identified a sensitive window of exposure at 37-40 weeks gestation between higher prenatal PM2.5 exposure and increased GSTP1 percent methylation. The association between higher GSTP1 percent methylation and decreased FEV1 was borderline significant in the sample as a whole (ß = - 0.37, SE = 0.20, p = 0.06) and in boys in stratified analyses (ß = - 0.56, SE = 0.29, p = 0.05). CONCLUSIONS: Prenatal PM2.5 exposure in late pregnancy was associated with impaired early childhood lung function and hypermethylation of GSTPI in DNA isolated from nasal epithelial cells. There was a trend towards higher GSTP1 percent methylation being associated with reduced FEV1. All findings were most evident among boys.

The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages.

The cytokine IL-1ß is intimately linked to many pathological inflammatory conditions. Mature IL-1ß secretion requires cleavage by the inflammasome. Recent evidence indicates that many cell death signal adaptors have regulatory roles in inflammasome activity. These include the apoptosis inducers FADD and caspase 8, and the necroptosis kinases receptor interacting protein kinase 1 (RIPK1) and RIPK3. PGAM5 is a mitochondrial phosphatase that has been reported to function downstream of RIPK3 to promote necroptosis and IL-1ß secretion. To interrogate the biological function of PGAM5, we generated Pgam5(-/-) mice. We found that Pgam5(-/-) mice were smaller compared with wild type littermates, and male Pgam5(-/-) mice were born at sub-Mendelian ratio. Despite these growth and survival defects, Pgam5(-/-) cells responded normally to multiple inducers of apoptosis and necroptosis. Rather, we found that PGAM5 is critical for IL-1ß secretion in response to NLRP3 and AIM2 inflammasome agonists. Moreover, vesicular stomatosis virus-induced IL-1ß secretion was impaired in Pgam5(-/-) bone marrow-derived macrophages, but not in Ripk3(-/-) bone marrow-derived dendritic cells, indicating that PGAM5 functions independent of RIPK3 to promote inflammasome activation. Mechanistically, PGAM5 promotes ASC polymerization, maintenance of mitochondrial integrity, and optimal reactive oxygen species production in response to inflammasome signals. Hence PGAM5 is a novel regulator of inflammasome and caspase 1 activity that functions independently of RIPK3.

Prenatal nitrate air pollution exposure and reduced child lung function: Timing and fetal sex effects.

BACKGROUND: Prenatal particulate air pollution exposure may alter lung growth and development in utero in a time-sensitive and sex-specific manner, resulting in reduced lung function in childhood. Such relationships have not been examined for nitrate (NO3-). METHODS: We implemented Bayesian distributed lag interaction models (BDLIMs) to identify sensitive prenatal windows for the influence of NO3- on lung function at age 7 years, assessing effect modification by fetal sex. Analyses included 191 mother-child dyads. Daily ambient NO3- exposure over pregnancy was estimated using a hybrid chemical transport (Geos-Chem)/land-use regression model. Spirometry was performed at mean (SD) age of 6.99 (0.89) years, with forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) z-scores accounting for child age, sex, height and race/ethnicity. RESULTS: Most mothers were Hispanic (65%) or Black (22%), had ≤ high school education (67%), and never smoked (71%); 17% children had asthma. BDILMs adjusted for maternal age and education and child's asthma identified an early sensitive window of 6-12 weeks gestation, during which increased NO3- was significantly associated with reduced FEV1 z-scores specifically among boys. BDLIM analyses demonstrated similar sex-specific patterns for FVC. CONCLUSION: Early gestational NO3- exposure is associated with reduced child lung function, especially in boys.

Prenatal Nitrate Exposure and Childhood Asthma. Influence of Maternal Prenatal Stress and Fetal Sex.

RATIONALE: Impact of ambient pollution upon children's asthma may differ by sex, and exposure dose and timing. Psychosocial stress can also modify pollutant effects. These associations have not been examined for in utero ambient nitrate exposure. OBJECTIVES: We implemented Bayesian-distributed lag interaction models to identify sensitive prenatal windows for the influence of nitrate (NO3-) on child asthma, accounting for effect modification by sex and stress. METHODS: Analyses included 752 mother-child dyads. Daily ambient NO3- exposure during pregnancy was derived using a hybrid chemical transport (Geos-Chem)/land-use regression model and natural log transformed. Prenatal maternal stress was indexed by a negative life events score (high [>2] vs. low [≤2]). The outcome was clinician-diagnosed asthma by age 6 years. MEASUREMENTS AND MAIN RESULTS: Most mothers were Hispanic (54%) or black (29%), had a high school education or less (66%), never smoked (80%), and reported low prenatal stress (58%); 15% of children developed asthma. BDILMs adjusted for maternal age, race, education, prepregnancy obesity, atopy, and smoking status identified two sensitive windows (7-19 and 33-40 wk gestation), during which increased NO3- was associated with greater odds of asthma, specifically among boys born to mothers reporting high prenatal stress. Cumulative effects of NO3- across pregnancy were also significant in this subgroup (odds ratio = 2.64, 95% confidence interval = 1.27-5.39; per interquartile range increase in ln NO3-). CONCLUSIONS: Prenatal NO3- exposure during distinct sensitive windows was associated with incident asthma in boys concurrently exposed to high prenatal stress.

Impact of Maternal Lifetime Interpersonal Trauma on Children's Asthma: Mediation Through Maternal Active Asthma During Pregnancy.

OBJECTIVE: Traumatic stressors, including child abuse and/or interpersonal violence over a woman's lifecourse, can affect the health of her children. This study examines the associations between maternal lifetime interpersonal trauma (IPT) and children's asthma by age 6 years (n = 857). METHODS: Pregnant women completed the Revised Conflict Tactics Scale; IPT exposure was categorized as unexposed (55%), early (childhood and/or teen years only, 25%), late (adulthood and/or index pregnancy, 7%), and chronic (early and late, 13%). Clinician-diagnosed asthma in children was reported by mothers at each follow-up visit until the child reached age 6 years. We examined the effects of maternal IPT categories and child's asthma using logistic regression. Using structural equation models, we also examined indirect relationships between maternal chronic IPT and child asthma operating through active asthma in pregnancy, prepregnancy BMI, prenatal smoking, and/or increased exposure to other adverse life events or environmental toxins prenatally. Effect modification by the child's sex was examined. RESULTS: Mothers were primarily Hispanic (55%) or black (30%) with less than high school education (62%). In logistic regression models, chronic maternal IPT (compared with unexposed) was associated with asthma in boys (odds ratio = 2.87, 95% confidence interval = 1.48-5.57) but not girls (odds ratio = 0.69, 95% confidence interval = 0.23-2.12; pinteraction = .042). In structural equation models, chronic IPT was associated with maternal active asthma in pregnancy (ß = 0.59, p < .001), maternal active asthma was associated with children's asthma (ß = 0.20, p = .009), and the total indirect effect for this path was significant (ß = 0.12, p = .031). Associations were most evident among boys. CONCLUSIONS: Mothers' history of chronic IPT was associated with asthma in boys. This association was mediated through active maternal asthma in pregnancy.